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- JP2017523187A5 JP2017523187A5 JP2017504713A JP2017504713A JP2017523187A5 JP 2017523187 A5 JP2017523187 A5 JP 2017523187A5 JP 2017504713 A JP2017504713 A JP 2017504713A JP 2017504713 A JP2017504713 A JP 2017504713A JP 2017523187 A5 JP2017523187 A5 JP 2017523187A5
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- 102000003812 Interleukin-15 Human genes 0.000 claims description 94
- 108090000172 Interleukin-15 Proteins 0.000 claims description 94
- 201000011510 cancer Diseases 0.000 claims description 17
- 201000009910 diseases by infectious agent Diseases 0.000 claims description 17
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- 206010025327 Lymphopenia Diseases 0.000 claims description 13
- 231100001023 lymphopenia Toxicity 0.000 claims description 13
- 238000002560 therapeutic procedure Methods 0.000 claims description 8
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 6
- 102000004965 antibodies Human genes 0.000 claims description 5
- 108090001123 antibodies Proteins 0.000 claims description 5
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- 206010000565 Acquired immunodeficiency syndrome Diseases 0.000 claims description 2
- 101710042656 BQ2027_MB1231C Proteins 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 206010025650 Malignant melanoma Diseases 0.000 claims description 2
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- 208000006265 Renal Cell Carcinoma Diseases 0.000 claims description 2
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- 230000001684 chronic Effects 0.000 claims description 2
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- 201000005202 lung cancer Diseases 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 201000008827 tuberculosis Diseases 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 14
- 102100005826 CD19 Human genes 0.000 claims 1
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- 102000003964 Histone deacetylases Human genes 0.000 description 2
- 108090000353 Histone deacetylases Proteins 0.000 description 2
- 102000004556 Interleukin-15 Receptors Human genes 0.000 description 1
- 108010017535 Interleukin-15 Receptors Proteins 0.000 description 1
- 108010002586 Interleukin-7 Proteins 0.000 description 1
- 208000008771 Lymphadenopathy Diseases 0.000 description 1
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- FWZRWHZDXBDTFK-ZHACJKMWSA-N Panobinostat Chemical group CC1=NC2=CC=C[CH]C2=C1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FWZRWHZDXBDTFK-ZHACJKMWSA-N 0.000 description 1
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Description
特許出願、特許および科学的刊行物を含めた様々な参照が、本明細書において引用され；各参照の開示は、参照によりその全体が本明細書に組み込まれる。
また、本発明は以下を提供する。
＜１＞ヒト対象のリンパ球減少症、癌もしくは感染症を治療する方法、またはヒト対象のＨＩＶ感染細胞においてＨＩＶを根絶するもしくは減少させる方法であって、
（ａ）前記ヒト対象に初期低用量のインターロイキン−１５（ＩＬ−１５）／ＩＬ−１５受容体アルファ（ＩＬ−１５Ｒα）複合体を少なくとも１回投与する工程と；
（ｂ）前記ヒト対象に連続的に高い用量のＩＬ−１５／ＩＬ−１５Ｒα複合体を投与して、ＩＬ−１５とリンパ球細胞数の有効比を達成する工程と
を含む、方法。
＜２＞ヒト対象のリンパ球減少症、癌もしくは感染症を治療する方法、またはヒト対象のＨＩＶ感染細胞においてＨＩＶを根絶するもしくは減少させる方法であって、
（ａ）前記ヒト対象に初期低用量のＩＬ−１５／ＩＬ−１５Ｒα複合体を少なくとも１回投与する工程と；
（ｂ）ある用量の前記ＩＬ−１５／ＩＬ−１５Ｒα複合体の前記投与後および別の用量の前記ＩＬ−１５／ＩＬ−１５Ｒα複合体の投与前の一定期間に前記対象から得たサンプル中の遊離ＩＬ−１５の濃度が、一本鎖ＩＬ−１５の質量に基づいて決定した場合の正常レベル内である場合に、前記ヒト対象に連続的に高い用量のＩＬ−１５／ＩＬ−１５Ｒα複合体を投与する工程と
を含む、方法。
＜３＞ヒト対象のリンパ球減少症、癌もしくは感染症を治療する方法、またはヒト対象のＨＩＶ感染細胞においてＨＩＶを根絶するもしくは減少させる方法であって、
（ａ）前記ヒト対象に初期低用量のＩＬ−１５／ＩＬ−１５Ｒα複合体を少なくとも１回投与する工程と；
（ｂ）ある用量の前記ＩＬ−１５／ＩＬ−１５Ｒα複合体の前記投与後および別の用量の前記ＩＬ−１５／ＩＬ−１５Ｒα複合体の投与前の一定期間に前記対象から得たサンプル中の遊離ＩＬ−１５の濃度がおよそ１ｐｇ／ｍＬ〜５０ｐｇ／ｍＬである場合に、前記ヒト対象に連続的に高い用量の前記ＩＬ−１５／ＩＬ−１５Ｒα複合体を投与する工程と
を含む、方法。
＜４＞ヒト対象のリンパ球減少症、癌もしくは感染症を治療する方法、またはヒト対象のＨＩＶ感染細胞においてＨＩＶを根絶するもしくは減少させる方法であって、
（ａ）前記ヒト対象に初期低用量の前記ＩＬ−１５／ＩＬ−１５Ｒα複合体を少なくとも１回投与する工程であって、初期低用量が、一本鎖ＩＬ−１５の質量に基づいて決定した場合、０．１μｇ／ｋｇ〜１μｇ／ｋｇである、工程と；
（ｂ）ある用量の前記ＩＬ−１５／ＩＬ−１５Ｒα複合体の前記投与後および別の用量の前記ＩＬ−１５／ＩＬ−１５Ｒα複合体の投与前の一定期間に前記対象から得たサンプル中の遊離ＩＬ−１５の濃度が正常レベル内である場合に、前記ヒト対象に連続的に高い用量の前記ＩＬ−１５／ＩＬ−１５Ｒα複合体を投与する工程であって、連続的に高い用量のそれぞれが、前の用量より２〜３倍高い、工程と
を含む、方法。
＜５＞ヒト対象のリンパ球減少症、癌もしくは感染症を治療する方法、またはヒト対象のＨＩＶ感染細胞においてＨＩＶを根絶するもしくは減少させる方法であって、
（ａ）前記ヒト対象に初期低用量のＩＬ−１５／ＩＬ−１５Ｒα複合体を少なくとも１回投与する工程であって、前記初期低用量が、一本鎖ＩＬ−１５の質量に基づいて決定した場合、０．１μｇ／ｋｇ〜１μｇ／ｋｇである、工程と；
（ｂ）ある用量のＩＬ−１５／ＩＬ−１５Ｒα複合体の投与後および別の用量のＩＬ−１５／ＩＬ−１５Ｒα複合体の投与前の一定期間に対象から得たサンプル中の遊離ＩＬ−１５の濃度がおよそ１ｐｇ／ｍＬ〜５０ｐｇ／ｍＬである場合に、ヒト対象に連続的に高い用量のＩＬ−１５／ＩＬ−１５Ｒα複合体を投与する工程であって、連続的に高い用量のそれぞれが、前の用量より２〜３倍高い、工程と
を含む、方法。
＜６＞ヒト対象のリンパ球減少症、癌もしくは感染症を治療する方法、またはヒト対象のＨＩＶ感染細胞においてＨＩＶを根絶するもしくは減少させる方法であって、
（ａ）前記ヒト対象に初期低用量のＩＬ−１５／ＩＬ−１５Ｒα複合体を１〜５回投与する工程と；
（ｂ）ある用量のＩＬ−１５／ＩＬ−１５Ｒα複合体の投与後および別の用量のＩＬ−１５／ＩＬ−１５Ｒα複合体の投与前の一定期間に対象から得たサンプル中の遊離ＩＬ−１５の濃度が正常レベル内である場合に、対象に連続的に高い用量のＩＬ−１５／ＩＬ−１５Ｒα複合体を投与する工程であって、各用量が１〜６回投与され、連続的に高い用量のそれぞれが、前の用量より２〜３倍高い、工程と
を含む、方法。
＜７＞ヒト対象のリンパ球減少症、癌もしくは感染症を治療する方法、またはヒト対象のＨＩＶ感染細胞においてＨＩＶを根絶するもしくは減少させる方法であって、一本鎖ＩＬ−１５の質量に基づいて決定した場合に０．１μｇ／ｋｇ〜１μｇ／ｋｇの初期低用量から始めて、用量を前の用量の２〜３倍に順次増加させる増加用量レジメンで、前記ヒト対象に前記ＩＬ−１５／ＩＬ−１５Ｒα複合体を投与する工程を含み、用量を次のレベルに上昇させる前に、各用量が少なくとも１、２または３回投与され、前記用量を次のレベルに上昇させる前に、ある用量のＩＬ−１５／ＩＬ−１５Ｒα複合体の投与後の一定期間に前記対象から得たサンプル中の遊離ＩＬ−１５の濃度が監視される、方法。
＜８＞ヒト対象のリンパ球減少症、癌もしくは感染症を治療する方法、またはヒト対象のＨＩＶ感染細胞においてＨＩＶを根絶するもしくは減少させる方法であって、以下の連続した用量：（ｉ）０．５μｇ／ｋｇ；（ｉｉ）１μｇ／ｋｇ；（ｉｖ）２μｇ／ｋｇ；（ｖ）４μｇ／ｋｇ；（ｖ）８μｇ／ｋｇ；および（ｖｉ）１６μｇ／ｋｇでの増加用量レジメンで、前記ヒト対象に前記ＩＬ−１５／ＩＬ−１５Ｒα複合体を投与する工程を含み、用量が、一本鎖ＩＬ−１５の質量に基づいて決定され、前記用量を次のレベルに上昇させる前に、各用量が少なくとも１、２または３回投与され、前記用量を次のレベルに上昇させる前に、ある用量のＩＬ−１５／ＩＬ−１５Ｒα複合体の投与後の一定期間に前記対象から得たサンプル中の遊離ＩＬ−１５の濃度が監視される、方法。
＜９＞前記初期低用量が、一本鎖ＩＬ−１５の質量に基づいて決定した場合、０．１μｇ／ｋｇ〜１μｇ／ｋｇである、＜１＞、＜２＞、＜３＞または＜６＞に記載の方法。
＜１０＞前記初期低用量が、一本鎖ＩＬ−１５の質量に基づいて決定した場合、０．１μｇ／ｋｇ〜０．５μｇ／ｋｇである、＜１＞、＜２＞、＜３＞または＜６＞に記載の方法。
＜１１＞前記初期低用量が、一本鎖ＩＬ−１５の質量に基づいて決定した場合、０．５μｇ／ｋｇである、＜１＞から＜８＞のいずれか一項に記載の方法。
＜１２＞連続的に高い用量のそれぞれが、前の用量より２〜３倍高い、＜１＞、＜２＞または＜３＞に記載の方法。
＜１３＞前記初期低用量が２〜５回投与される、＜１＞、＜２＞または＜３＞に記載の方法。
＜１４＞前記初期低用量が７〜１４日の間に１〜６回投与される、＜１＞から＜１３＞のいずれか一項に記載の方法。
＜１５＞各用量が、７〜１４日の間に少なくとも１、２または３回投与される、＜１＞から＜１３＞のいずれか一項に記載の方法。
＜１６＞一定期間が、ある用量のＩＬ−１５／ＩＬ−１５Ｒα複合体の投与後および別の用量のＩＬ−１５／ＩＬ−１５Ｒα複合体の投与前のおよそ２４時間〜およそ４８時間後である、＜２＞から＜８＞のいずれか一項に記載の方法。
＜１７＞前記対象が、リンパ節腫大および／または脾腫の徴候について監視される、＜１＞から＜１６＞のいずれか一項に記載の方法。
＜１８＞対象由来サンプル中の遊離ＩＬ−１５のトラフレベルが５０ｐｇ／ｍＬを超える場合、前記用量が増加されない、＜１＞から＜１７＞のいずれか一項に記載の方法。
＜１９＞（ｃ）前記対象に維持用量の前記ＩＬ−１５／ＩＬ−１５Ｒα複合体を投与する工程をさらに含み、前記維持用量が、前記対象由来サンプル中でおよそ１ｐｇ／ｍＬ〜５０ｐｇ／ｍＬの遊離ＩＬ−１５のトラフレベルを達成する、＜１＞から＜６＞のいずれか一項に記載の方法。
＜２０＞（ｃ）前記対象に維持用量の前記ＩＬ−１５／ＩＬ−１５Ｒα複合体を投与する工程をさらに含み、前記維持用量が、前記対象由来サンプル中でおよその正常なヒトレベルの遊離ＩＬ−１５のトラフレベルを達成する、＜１＞から＜６＞のいずれか一項に記載の方法。
＜２１＞前記対象に前記維持用量のＩＬ−１５／ＩＬ−１５Ｒα複合体を投与する工程をさらに含み、前記維持用量が、前記対象由来サンプル中でおよそ１ｐｇ／ｍＬ〜５０ｐｇ／ｍＬの遊離ＩＬ−１５のトラフレベルを達成する、＜７＞または＜８＞に記載の方法。
＜２２＞前記サンプルが血漿サンプルである、＜２＞から＜８＞または＜１８＞から＜２１＞のいずれか一項に記載の方法。
＜２３＞前記対象に０．１μｇ／ｋｇ〜１０μｇ／ｋｇのＩＬ−１５／ＩＬ−１５Ｒα複合体の維持用量を投与する工程をさらに含み、前記用量が、一本鎖ＩＬ−１５の質量に基づいて決定される、＜８＞に記載の方法。
＜２４＞前記癌が、黒色腫、大腸癌、肺癌、前立腺癌または腎細胞癌である、＜１＞から＜２３＞のいずれか一項に記載の方法。
＜２５＞前記癌が転移している、＜１＞から＜２４＞のいずれか一項に記載の方法。
＜２６＞前記感染症がＡＩＤＳである、＜１＞から＜２３＞のいずれか一項に記載の方法。
＜２７＞前記感染症が慢性的である、＜１＞から＜２３＞のいずれか一項に記載の方法。
＜２８＞前記感染症が肺炎または結核である、＜１＞から＜２３＞のいずれか一項に記載の方法。
＜２９＞前記ＩＬ−１５／ＩＬ−１５Ｒα複合体が、対象に皮下投与される、先行のいずれか一項に記載の方法。
＜３０＞前記ＩＬ−１５／ＩＬ−１５Ｒα複合体が、対象に静脈内または筋肉内投与される、＜１＞から＜２８＞のいずれか一項に記載の方法。
＜３１＞前記ＩＬ−１５／ＩＬ−１５Ｒα複合体が、対象に腫瘍内投与される＜１＞から＜２８＞のいずれか一項に記載の方法。
＜３２＞別の療法を投与する工程をさらに含む、先行のいずれか一項に記載の方法。
＜３３＞前記ＩＬ−１５／ＩＬ−１５Ｒα複合体が、天然のＩＬ−１５と天然の可溶性ＩＬ−１５Ｒαとのヘテロ二量体複合体である、先行のいずれか一項に記載の方法。
＜３４＞前記ＩＬ−１５が、ヒトＩＬ−１５であり、ＩＬ−１５Ｒαが、ヒトＩＬ−１５Ｒαの可溶型である、＜１＞から＜３２＞のいずれか一項に記載の方法。
＜３５＞前記天然のＩＬ−１５が、ヒトＩＬ−１５であり、天然の可溶性ＩＬ−１５Ｒαが、可溶性ヒトＩＬ−１５ａである、＜３３＞に記載の方法。
＜３６＞（ａ）前記ＩＬ−１５が、配列番号１のアミノ酸配列のアミノ酸残基４９〜１６２を含み；
（ｂ）前記ＩＬ−１５Ｒαが、配列番号３３、３５、３７、３９、４１または４５のアミノ酸配列を含む、＜１＞から＜３２＞のいずれか一項に記載の方法。
＜３７＞（ａ）ヒトＩＬ−１５が、配列番号１のアミノ酸配列のアミノ酸残基４９〜１６２を含み；
（ｂ）可溶性ヒトＩＬ−１５Ｒαが、配列番号３３のアミノ酸配列を含む、＜３５＞に記載の方法。
＜３８＞ヒト対象のリンパ球減少症、癌もしくは感染症を治療する方法、またはヒト対象のＨＩＶ感染細胞においてＨＩＶを根絶するもしくは減少させる方法であって、前記ヒト対象に対して１〜５回の初期低用量のＩＬ−１５／ＩＬ−１５Ｒα複合体から始めて、用量を前の用量より少なくとも２５％、５０％、７５％、１００％、１５０％、または２００％まで順次増加させる増加用量レジメンで、ヒト対象にＩＬ−１５／ＩＬ−１５Ｒα複合体を投与する工程を含み、前記用量を次のレベルに上昇させる前に、各用量が少なくとも１、２または３回投与される、方法。
＜３９＞ヒト対象のリンパ球減少症、癌もしくは感染症を治療する方法、またはヒト対象のＨＩＶ感染細胞においてＨＩＶを根絶するもしくは減少させる方法であって、一本鎖ＩＬ−１５の質量に基づいて決定した場合に０．２μｇ／ｋｇ〜１０μｇ／ｋｇの範囲の初期低用量から始めて、用量を前の用量より少なくとも２５％、５０％、７５％、１００％、１５０％、または２００％まで順次増加させる増加用量レジメンで、ヒト対象にＩＬ−１５／ＩＬ−１５Ｒα複合体を投与する工程を含み、前記用量を次のレベルに上昇させる前に、各用量が少なくとも１、２または３回投与される、方法。
＜４０＞ヒト対象のリンパ球減少症、癌もしくは感染症を治療する方法、またはヒト対象のＨＩＶ感染細胞においてＨＩＶを根絶するもしくは減少させる方法であって、以下の連続した用量：（ｉ）２μｇ／ｋｇ；（ｉｉ）４μｇ／ｋｇ；（ｉｖ）８μｇ／ｋｇ；（ｖ）１６μｇ／ｋｇ；（ｖ）３２μｇ／ｋｇ；および（ｖｉ）６４μｇ／ｋｇでの増加用量レジメンで、ヒト対象にＩＬ−１５／ＩＬ−１５Ｒα複合体を投与する工程を含み、前記用量が、一本鎖ＩＬ−１５の質量に基づいて決定され、前記用量を次のレベルに上昇させる前に、各用量が少なくとも１、２または３回投与される、方法。
＜４１＞ヒト対象のリンパ球減少症、癌もしくは感染症を治療する方法、またはヒト対象のＨＩＶ感染細胞においてＨＩＶを根絶するもしくは減少させる方法であって、以下の連続した用量：（ｉ）５μｇ／ｋｇ；（ｉｉ）１０μｇ／ｋｇ；（ｉｖ）２０μｇ／ｋｇ；（ｖ）４０μｇ／ｋｇ；（ｖ）８０μｇ／ｋｇ；および（ｖｉ）１２０μｇ／ｋｇでの増加用量レジメンで、ヒト対象にＩＬ−１５／ＩＬ−１５Ｒα複合体を投与する工程を含み、前記用量が、一本鎖ＩＬ−１５の質量に基づいて決定され、前記用量を次のレベルに上昇させる前に、各用量が少なくとも１、２または３回投与される、方法。
＜４２＞用量を次のレベルに上昇させる前に、ある用量の前記ＩＬ−１５／ＩＬ−１５Ｒα複合体の投与後の一定期間に前記対象から得たサンプル中の遊離ＩＬ−１５の濃度が監視される、＜３８＞、＜３９＞、＜４０＞または＜４１＞に記載の方法。
＜４３＞各用量が、２週間にわたり、週３回、１度投与される、＜３８＞、＜３９＞、＜４０＞または＜４１＞に記載の方法。
＜４４＞ヒト対象に１つ以上の他の療法を投与する工程をさらに含む、＜１＞から＜８＞および＜３８＞から＜４１＞のいずれか一項に記載の方法。
＜４５＞前記１つ以上の他の療法が、Ｈｅｒ２、ＰＤ−１またはＰＤ−１のリガンドに免疫特異的に結合する抗体である、＜４４＞に記載の方法。
＜４６＞前記１つ以上の他の療法が、ヒストン脱アセチル化酵素（ＨＤＡＣ）阻害剤、ＴＬＲ７アゴニストまたはサイトカインである、＜４４＞に記載の方法。
＜４７＞前記サイトカインが、ＩＬ−７である、＜４６＞に記載の方法。
＜４８＞前記ＨＤＡＣ阻害剤が、パノビノスタットまたはボリノスタットである、＜４６＞に記載の方法。
＜４９＞前記ヒト対象が、ＨＩＶを有する、＜４６＞に記載の方法。
＜５０＞前記ヒト対象が、１つ以上の抗レトロウイルス療法で治療されたことがあるか、または現在治療されている、＜４９＞に記載の方法。
Various references, including patent applications, patents and scientific publications, are cited herein; the disclosure of each reference is incorporated herein by reference in its entirety.
The present invention also provides the following.
<1> A method of treating lymphopenia, cancer or infection in a human subject, or a method of eradicating or reducing HIV in HIV-infected cells of a human subject,
(A) administering to said human subject an initial low dose of interleukin-15 (IL-15) / IL-15 receptor alpha (IL-15Rα) complex at least once;
(B) administering a continuous high dose of IL-15 / IL-15Rα complex to said human subject to achieve an effective ratio of IL-15 to lymphocyte cell number;
Including a method.
<2> a method of treating lymphopenia, cancer or infection in a human subject, or a method of eradicating or reducing HIV in HIV-infected cells of a human subject,
(A) administering to said human subject at least one initial low dose of IL-15 / IL-15Rα complex;
(B) in a sample obtained from the subject for a period of time after the administration of a dose of the IL-15 / IL-15Rα complex and before administration of another dose of the IL-15 / IL-15Rα complex; When the concentration of free IL-15 is within normal levels as determined based on the mass of single-chain IL-15, the human subject has a continuously high dose of IL-15 / IL-15Rα complex. The step of administering
Including a method.
<3> A method of treating lymphopenia, cancer or infection in a human subject, or a method of eradicating or reducing HIV in HIV-infected cells of a human subject,
(A) administering to said human subject at least one initial low dose of IL-15 / IL-15Rα complex;
(B) in a sample obtained from the subject for a period of time after the administration of a dose of the IL-15 / IL-15Rα complex and before administration of another dose of the IL-15 / IL-15Rα complex; Administering a continuous high dose of the IL-15 / IL-15Rα complex to the human subject when the concentration of free IL-15 is approximately 1 pg / mL to 50 pg / mL;
Including a method.
<4> A method of treating lymphopenia, cancer or infection in a human subject, or a method of eradicating or reducing HIV in HIV-infected cells of a human subject,
(A) administering at least one initial low dose of the IL-15 / IL-15Rα complex to the human subject, the initial low dose being determined based on the mass of single-chain IL-15 A step of 0.1 μg / kg to 1 μg / kg;
(B) in a sample obtained from the subject for a period of time after the administration of a dose of the IL-15 / IL-15Rα complex and before administration of another dose of the IL-15 / IL-15Rα complex; Administering a continuous high dose of the IL-15 / IL-15Rα complex to the human subject when the concentration of free IL-15 is within normal levels, each of the sequentially high doses Is 2-3 times higher than the previous dose,
Including a method.
<5> a method of treating lymphopenia, cancer or infection in a human subject, or a method of eradicating or reducing HIV in HIV-infected cells of a human subject,
(A) administering at least one initial low dose of IL-15 / IL-15Rα complex to said human subject, said initial low dose being determined based on the mass of single chain IL-15 A step of 0.1 μg / kg to 1 μg / kg;
(B) Free IL-15 in a sample obtained from a subject after administration of a dose of IL-15 / IL-15Rα complex and for a period of time before administration of another dose of IL-15 / IL-15Rα complex. Administering a continuous high dose of IL-15 / IL-15Rα complex to a human subject, wherein each of the successively high doses is about 1 pg / mL to 50 pg / mL 2 to 3 times higher than the previous dose, and
Including a method.
<6> A method for treating lymphopenia, cancer or infection in a human subject, or a method for eradicating or reducing HIV in HIV-infected cells in a human subject,
(A) administering an initial low dose of IL-15 / IL-15Rα complex 1-5 times to said human subject;
(B) Free IL-15 in a sample obtained from a subject after administration of a dose of IL-15 / IL-15Rα complex and for a period of time before administration of another dose of IL-15 / IL-15Rα complex. Administering a continuous high dose of IL-15 / IL-15Rα complex to a subject when each concentration is within normal levels, each dose being administered 1 to 6 times, continuously high Each of the doses is 2-3 times higher than the previous dose, and
Including a method.
<7> A method of treating lymphopenia, cancer or infection in a human subject, or a method of eradicating or reducing HIV in HIV-infected cells of a human subject, based on the mass of single-chain IL-15 Starting with an initial low dose of 0.1 [mu] g / kg to 1 [mu] g / kg, as determined in the above, in an increasing dose regimen in which the dose is increased to 2-3 times the previous dose, the human subject is treated with the IL-15 / IL Administering a -15Rα complex, wherein each dose is administered at least 1, 2 or 3 times before increasing the dose to the next level, and before increasing the dose to the next level, a dose of A method wherein the concentration of free IL-15 in a sample obtained from said subject is monitored over a period of time after administration of the IL-15 / IL-15Rα complex.
<8> A method of treating lymphopenia, cancer or infection in a human subject, or a method of eradicating or reducing HIV in HIV-infected cells of a human subject, comprising the following sequential doses: (i) 0 (Ii) 1 μg / kg; (iv) 2 μg / kg; (v) 4 μg / kg; (v) 8 μg / kg; and (vi) an increasing dose regimen at 16 μg / kg. Administering the IL-15 / IL-15Rα complex to each other, wherein doses are determined based on the mass of single-chain IL-15, and before increasing the dose to the next level, Release in a sample obtained from the subject at a certain time after administration of a dose of IL-15 / IL-15Rα complex, administered at least 1, 2 or 3 times and before raising the dose to the next level IL- A method wherein 15 concentrations are monitored.
<9> The initial low dose is 0.1 μg / kg to 1 μg / kg, as determined based on the mass of single-chain IL-15, <1>, <2>, <3> or <6 > Method.
<10> The initial low dose is 0.1 μg / kg to 0.5 μg / kg when determined based on the mass of single-chain IL-15, <1>, <2>, <3> or <6> The method according to item 6.
<11> The method according to any one of <1> to <8>, wherein the initial low dose is 0.5 μg / kg when determined based on the mass of single-chain IL-15.
<12> The method according to <1>, <2> or <3>, wherein each successively higher dose is 2-3 times higher than the previous dose.
<13> The method according to <1>, <2> or <3>, wherein the initial low dose is administered 2 to 5 times.
<14> The method according to any one of <1> to <13>, wherein the initial low dose is administered 1 to 6 times during 7-14 days.
<15> The method according to any one of <1> to <13>, wherein each dose is administered at least 1, 2 or 3 times during 7-14 days.
<16> The fixed period is approximately 24 hours to approximately 48 hours after administration of one dose of IL-15 / IL-15Rα complex and before administration of another dose of IL-15 / IL-15Rα complex The method as described in any one of <2> to <8>.
<17> The method according to any one of <1> to <16>, wherein the subject is monitored for signs of lymphadenopathy and / or splenomegaly.
<18> The method according to any one of <1> to <17>, wherein the dose is not increased when the trough level of free IL-15 in the subject-derived sample exceeds 50 pg / mL.
<19> (c) further comprising administering a maintenance dose of the IL-15 / IL-15Rα complex to the subject, wherein the maintenance dose is about 1 pg / mL to 50 pg / mL in the subject-derived sample. The method according to any one of <1> to <6>, wherein a trough level of free IL-15 is achieved.
<20> (c) further comprising administering to the subject a maintenance dose of the IL-15 / IL-15Rα complex, wherein the maintenance dose is about normal human level free IL in the subject-derived sample. The method according to any one of <1> to <6>, wherein a trough level of −15 is achieved.
<21> further comprising administering the maintenance dose of the IL-15 / IL-15Rα complex to the subject, wherein the maintenance dose is about 1 pg / mL to 50 pg / mL free IL- in the subject-derived sample. The method according to <7> or <8>, wherein 15 trough levels are achieved.
<22> The method according to any one of <2> to <8> or <18> to <21>, wherein the sample is a plasma sample.
<23> further comprising administering to the subject a maintenance dose of 0.1 μg / kg to 10 μg / kg of IL-15 / IL-15Rα complex, wherein the dose is based on the mass of single-chain IL-15 <8> The method according to <8>.
<24> The method according to any one of <1> to <23>, wherein the cancer is melanoma, colon cancer, lung cancer, prostate cancer, or renal cell carcinoma.
<25> The method according to any one of <1> to <24>, wherein the cancer has metastasized.
<26> The method according to any one of <1> to <23>, wherein the infectious disease is AIDS.
<27> The method according to any one of <1> to <23>, wherein the infectious disease is chronic.
<28> The method according to any one of <1> to <23>, wherein the infectious disease is pneumonia or tuberculosis.
<29> The method according to any one of the preceding claims, wherein the IL-15 / IL-15Rα complex is administered subcutaneously to a subject.
<30> The method according to any one of <1> to <28>, wherein the IL-15 / IL-15Rα complex is administered to a subject intravenously or intramuscularly.
<31> The method according to any one of <1> to <28>, wherein the IL-15 / IL-15Rα complex is administered to a subject intratumorally.
<32> The method according to any one of the preceding claims, further comprising the step of administering another therapy.
<33> The method according to any one of the preceding claims, wherein the IL-15 / IL-15Rα complex is a heterodimeric complex of natural IL-15 and natural soluble IL-15Rα.
<34> The method according to any one of <1> to <32>, wherein the IL-15 is human IL-15, and IL-15Rα is a soluble form of human IL-15Rα.
<35> The method according to <33>, wherein the natural IL-15 is human IL-15, and the natural soluble IL-15Rα is soluble human IL-15a.
<36> (a) The IL-15 includes amino acid residues 49 to 162 of the amino acid sequence of SEQ ID NO: 1;
(B) The method according to any one of <1> to <32>, wherein the IL-15Rα comprises the amino acid sequence of SEQ ID NO: 33, 35, 37, 39, 41, or 45.
<37> (a) human IL-15 comprises amino acid residues 49 to 162 of the amino acid sequence of SEQ ID NO: 1;
(B) The method according to <35>, wherein the soluble human IL-15Rα comprises the amino acid sequence of SEQ ID NO: 33.
<38> A method for treating lymphopenia, cancer or infection in a human subject, or a method for eradicating or reducing HIV in HIV-infected cells in a human subject, wherein the method is 1-5 times for the human subject. Starting with an initial low dose of IL-15 / IL-15Rα complex, and increasing dose regimen that sequentially increases the dose to at least 25%, 50%, 75%, 100%, 150%, or 200% over the previous dose Administering the IL-15 / IL-15Rα complex to a human subject, wherein each dose is administered at least 1, 2 or 3 times before increasing the dose to the next level.
<39> A method of treating lymphopenia, cancer or infection in a human subject, or a method of eradicating or reducing HIV in HIV-infected cells of a human subject, based on the mass of single-chain IL-15 Starting with an initial low dose in the range of 0.2 μg / kg to 10 μg / kg, as determined in order, the dose is at least 25%, 50%, 75%, 100%, 150%, or 200% sequentially from the previous dose Administering an IL-15 / IL-15Rα complex to a human subject in an increasing dose regimen, wherein each dose is administered at least 1, 2 or 3 times before raising said dose to the next level. The way.
<40> A method of treating lymphopenia, cancer or infection in a human subject, or a method of eradicating or reducing HIV in HIV-infected cells of a human subject, comprising the following sequential doses: (i) 2 μg (Ii) 4 μg / kg; (iv) 8 μg / kg; (v) 16 μg / kg; (v) 32 μg / kg; and (vi) increasing dose regimen at 64 μg / kg in human subjects with IL- Administering a 15 / IL-15Rα complex, wherein the dose is determined based on the mass of single-chain IL-15, and each dose is at least 1, before raising the dose to the next level, Method administered 2 or 3 times.
<41> A method of treating lymphopenia, cancer or infection in a human subject, or a method of eradicating or reducing HIV in HIV-infected cells of a human subject, comprising the following sequential doses: (i) 5 μg (Ii) 10 μg / kg; (iv) 20 μg / kg; (v) 40 μg / kg; (v) 80 μg / kg; and (vi) increasing dose regimen at 120 μg / kg in human subjects with IL- Administering a 15 / IL-15Rα complex, wherein the dose is determined based on the mass of single-chain IL-15, and each dose is at least 1, before raising the dose to the next level, Method administered 2 or 3 times.
<42> Before increasing the dose to the next level, the concentration of free IL-15 in the sample obtained from the subject is monitored for a period of time after administration of a dose of the IL-15 / IL-15Rα complex. <38>, <39>, <40> or <41>.
<43> The method according to <38>, <39>, <40> or <41>, wherein each dose is administered once three times a week for 2 weeks.
<44> The method of any one of <1> to <8> and <38> to <41>, further comprising administering one or more other therapies to the human subject.
<45> The method according to <44>, wherein the one or more other therapies are antibodies that immunospecifically bind to a ligand of Her2, PD-1, or PD-1.
<46> The method according to <44>, wherein the one or more other therapies are a histone deacetylase (HDAC) inhibitor, a TLR7 agonist, or a cytokine.
<47> The method according to <46>, wherein the cytokine is IL-7.
<48> The method according to <46>, wherein the HDAC inhibitor is panobinostat or vorinostat.
<49> The method of <46>, wherein the human subject has HIV.
<50> The method of <49>, wherein the human subject has been treated with or is currently being treated with one or more antiretroviral therapies.
Claims (15)
（ａ）初期低用量で投与され、該初期低用量が、一本鎖ＩＬ−１５の質量に基づいて決定した場合、０．１μｇ／ｋｇと１μｇ／ｋｇの間であり、且つ、
（ｂ）連続的に高い用量で投与され、ある用量の前記ＩＬ−１５／ＩＬ−１５Ｒα複合体の前記投与後および別の用量の前記ＩＬ−１５／ＩＬ−１５Ｒα複合体の投与前の一定期間に前記対象から得たサンプル中の遊離ＩＬ−１５の濃度が正常レベル内である場合に、連続的に高い用量のそれぞれが、前の用量より２〜３倍高く、または、
（ｂ）連続的に高い用量で投与され、ある用量の前記ＩＬ−１５／ＩＬ−１５Ｒα複合体の前記投与後および別の用量の前記ＩＬ−１５／ＩＬ−１５Ｒα複合体の投与前の一定期間に前記対象から得たサンプル中の遊離ＩＬ−１５の濃度がおよそ１ｐｇ／ｍＬ〜５０ｐｇ／ｍＬである場合に、連続的に高い用量のそれぞれが、前の用量より２〜３倍高い、医薬組成物。 IL-15 / IL-15Rα includes a complex medicament for reducing or eradicating HIV in a human subject lymphopenia, for treating cancer or infectious diseases, or in HIV-infected cells in a human subject A composition comprising the IL-15 / IL-15Rα complex,
(A) initial is administered at low-dose, if initial low dose was determined based on the weight of the single-chain IL-15, it is between 0.1 [mu] g / kg and 1 [mu] g / kg, and,
(B) are administered in amounts use continuous manner high a dose of the IL-15 / IL-15Rα after the administration of the conjugate and another dose of the IL-15 / IL-15Rα complex prior to administration of Each of the successively higher doses is 2-3 times higher than the previous dose if the concentration of free IL-15 in the sample obtained from the subject over a period of time is within normal levels, or
(B) a period of time after administration of one dose of the IL-15 / IL-15Rα complex and before administration of another dose of the IL-15 / IL-15Rα complex, administered at successively higher doses Wherein the concentration of free IL-15 in the sample obtained from said subject is approximately 1 pg / mL to 50 pg / mL, and each successive high dose is 2-3 times higher than the previous dose object.
前記維持用量が、前記対象由来サンプル中でおよそ正常ヒトレベルの遊離ＩＬ−１５のトラフレベルを達成する、請求項１に記載の医薬組成物。 2. The pharmaceutical composition of claim 1, wherein the maintenance dose achieves approximately normal human levels of free IL-15 trough levels in the subject-derived sample.
（ｂ）可溶性ヒトＩＬ−１５Ｒαが、配列番号３３のアミノ酸配列を含む、 (B) the soluble human IL-15Rα comprises the amino acid sequence of SEQ ID NO: 33,
請求項１０に記載の医薬組成物。The pharmaceutical composition according to claim 10.
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